JP2022063252A - Liquid formulation of brimonidine - Google Patents

Abstract

To provide an ophthalmologic liquid formulation that contains brimonidine and/or a salt thereof and a preservative, where the liquid formulation is less prone to reduced transition to the conjunctiva.SOLUTION: It has been found out that adding an amino acid can prevent reduced transition to the conjunctiva. Thus, there are provide an ophthalmologic liquid formulation that contains brimonidine and/or a salt thereof, a preservative, and an amino acid.SELECTED DRAWING: None

Description

The present invention relates to a liquid preparation containing brimonidine and / or a salt thereof.

Brimonidine and its salts are known as α-2 adrenergic receptor agonists. The human eye has many α-2 adrenergic receptors (hereinafter, may be abbreviated as α-2 receptors), and α-2 receptor agonists are used to suppress aqueous humor production and the uveal tract. It has the effect of lowering intraocular pressure by promoting the outflow of aqueous humor through the scleral outflow tract. Based on this effect, α-2 receptor agonists have conventionally been used for the treatment of glaucoma and ocular hypertension. In addition, α-2 receptor agonists have the effect of causing a reduction in the lumen size of α-2 receptor concentrated arterioles, especially terminal arterioles. This action causes vasoconstriction, reduces redness of the eye, increases whiteness, and improves the aesthetic appearance of the eye (Patent Document 1: Japanese Patent No. 5671459; Patent Document 2: Patent Document 2: Patent Document 2: Patent Document 2: Patent Document 2: Patent Document 2: Patent Document 2: Patent Document 2: No. 5738890).

For a pharmaceutical product in which brimonidine and / or a salt thereof and timolol and / or a salt thereof are used in combination, a pharmaceutical formulation technique focusing on the pharmaceutical stability is being studied. For example, in Patent Document 3 (Japanese Patent Laid-Open No. 2009-533462), a composition containing about 1 to 4.5 mM brimonidine and about 2 to 16 mM timolol and having a pH of about 7 to 8.5 is described. It is disclosed that the formation of decomposition products can be suppressed and the stability is improved. Further, in Patent Document 4 (Japanese Unexamined Patent Publication No. 2017-222707), an eye drop containing brimonidine and / or a salt thereof, and brinzolamide and / or a salt thereof has a maximum transmittance of 67% for light having a wavelength of 360 to 460 nm. By accommodating brimonidine and / or a salt thereof in a transparent container having the following and a maximum transmittance of 78% or less of light having a wavelength of 600 to 680 nm, decomposition of brimonidine and / or a salt thereof due to light exposure can be suppressed, and formulation stability is ensured. It is disclosed that it can be done. Further, in Patent Document 5 (Japanese Unexamined Patent Publication No. 2020-33290), an aqueous composition containing brimonidine contains an amino compound typified by chlorhexidine, whereby brimonidine in the aqueous composition is stored at a high temperature. It is disclosed that the decrease in content can be suppressed.

When formulated as an eye drop, a well-known additive is added together with one or more active ingredients. It is not possible to arbitrarily combine active ingredients and additives in the formulation, and considering the compatibility between the active ingredients and the compatibility between the active ingredients and the additives, the stability, efficacy, safety, etc. of the entire formulation, etc. Need to be evaluated.

Japanese Patent No. 5671459 Japanese Patent No. 5738890 Japanese Patent Publication No. 2009-533462 Japanese Unexamined Patent Publication No. 2017-222707 Japanese Unexamined Patent Publication No. 2020-33290

In order to formulate brimonidine and / or a salt thereof as an ophthalmic liquid preparation that relieves or suppresses red eye, it must have high stability, and at the site of action of brimonidine and / or its salt. It needs to have the transferability to a certain conjunctiva. In addition, a preservative is usually added to the multidose ophthalmic liquid preparation from the viewpoint of maintaining quality. On the other hand, when a preservative is added to an ophthalmic liquid preparation containing brimonidine and / or its salt, the problem is that the amount of brimonidine and / or its salt transferred to the oil layer, which is an indicator of conjunctival transferability, is reduced. ..

Therefore, when the present inventors searched for a compound that suppresses the decrease in the amount of brimonidine and / or its salt transferred to the oil layer, the decrease in the amount of brimonidine and / or its salt transferred to the oil layer due to a preservative for amino acids was found. It was found that it has the effect of suppressing. Furthermore, it has been found that the photostability is also improved in the ophthalmic liquid preparation containing brimonidine and / or a salt thereof to which the selected amino acids are added.

As an embodiment of the present invention, the following liquid preparation for ophthalmology is provided.
[1] An ophthalmic liquid preparation containing 0.01 to 0.05 w / v% brimonidine and / or a salt thereof, a preservative, and amino acids.
[2] The liquid preparation for ophthalmology according to item 1, wherein the preservative is a bactericidal surfactant.
[3] The liquid preparation for ophthalmology according to item 2, wherein the bactericidal surfactant is selected from the group consisting of a benzalkonium salt, an alkyldiaminoethylglycine salt, and a polyhexamethylene biguanide salt.
[4] The liquid preparation for ophthalmology according to any one of items 1 to 3, wherein the amino acids are at least one selected from aspartic acid and / or a salt thereof and taurine.
[5] The liquid preparation for ophthalmology according to any one of items 1 to 4, wherein the concentration of amino acids is 0.01 to 10 w / v%.

Further, as an embodiment of the present invention, the following method for promoting conjunctival migration is provided.
[6] Brimonidine and / or brimonidine in eye drop administration, which comprises adding amino acids to an ophthalmic liquid preparation containing 0.01 to 0.05 w / v% brimonidine and / or a salt thereof, and a preservative. Or a method for promoting conjunctival transfer of the salt.

Further, as an embodiment of the present invention, the following conjunctival transfer promoter is provided.
[7] A conjunctival transfer promoter of brimonidine and / or a salt thereof used in an ophthalmic liquid preparation containing 0.01 to 0.05 w / v% of brimonidine and / or a salt thereof, and a preservative. The conjunctival transfer promoter containing amino acids.

Further, as an embodiment of the present invention, the following photostabilization method is provided.
[8] In an ophthalmic liquid preparation containing 0.01 to 0.05 w / v% brimonidine and / or a salt thereof, and a preservative, the ophthalmic liquid preparation comprising amino acids is blended. A method for photostabilizing brimonidine and / or a salt thereof.

Further, as an embodiment of the present invention, the following light stabilizer is provided.
[9] A light stabilizer for brimonidine and / or a salt thereof, which is used in an ophthalmic liquid preparation containing 0.01 to 0.05 w / v% brimonidine and / or a salt thereof, and a preservative. , The light stabilizer containing amino acids.

According to the present invention, the addition of amino acids to an ophthalmic liquid preparation containing a preservative and brimonidine and / or a salt thereof exerts an effect of improving conjunctival transferability. In addition, an ophthalmic liquid preparation containing brimonidine and / or a salt thereof, a preservative and amino acids has improved photostability.

It is understood that the terms used herein are used in the meaning commonly used in the art unless otherwise noted. Accordingly, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The numerical range specified herein shall include its lower and upper limits.

(Definition)
As used herein, "brimonidine" is referred to as IUPAC name: 5-bromo-N- (4,5-dihydro-1H-imidazol-2-yl) quinoxaline-6-amine (5-Bromo-N- (4,5)). -Dihydro-1H-imidazole-2-yl) quinoxaline-6-amine) refers to a compound. Further, in the present specification, the concentration of brimonidine and / or a salt thereof is the concentration converted to brimonidine tartrate unless otherwise specified.

As used herein, the term "low concentration brimonidine" refers to brimonidine having a concentration of 0.05 w / v% or less.

As used herein, the term "ophthalmic liquid preparation" refers to an aqueous liquid preparation based on water, and refers to an ophthalmic preparation, particularly a preparation used for instillation.

As used herein, "photostability" refers to the degree to which the content of brimonidine and / or a salt thereof is maintained in a liquid product for ophthalmology after exposure to a certain amount of light.

As used herein, "photostabilization" refers to suppressing a decrease in the content of brimonidine and / or a salt thereof in an ophthalmic liquid preparation due to exposure to a certain amount of light in the ophthalmic liquid preparation, and brimonidine and / or its salt. It means to maintain a higher residual rate of salt. As an example, an ophthalmic liquid preparation containing brimonidine and / or a salt thereof is filled in a colorless glass ampoule, exposed to white light of 600,000 xl · hr, and then compared with the case where it does not contain a preservative and amino acids. , The content of brimonidine and / or its salt is maintained, that is, the residual rate of brimonidine and / or its salt is higher.

As used herein, the term "light stabilization method" refers to suppressing a decrease in the content of brimonidine and / or a salt thereof in an ophthalmic liquid preparation due to exposure to a certain amount of light in the ophthalmic liquid preparation, and brimonidine and / or It means a method performed to maintain a higher residual rate of the salt.

As used herein, the term "light stabilizer" suppresses a decrease in the content of brimonidine and / or a salt thereof in an ophthalmic liquid preparation due to exposure to a certain amount of light, and determines the residual ratio of brimonidine and / or a salt thereof. It means an agent that is formulated to keep it higher.

As used herein, the term "conjunctival transferability" is an index indicating the ease with which brimonidine and / or a salt thereof in an ophthalmic liquid preparation administered by eye drops is easily transferred to the conjunctiva, which is the site of action.

As used herein, the term "method for promoting conjunctival transfer" is a method used to increase the amount of brimonidine and / or a salt thereof transferred to the conjunctiva, which is the site of action, in an ophthalmic liquid preparation administered by eye drops. Means.

As used herein, the term "conjunctival transfer promoter" is formulated to increase the amount of brimonidine and / or a salt thereof in an ophthalmic liquid preparation administered by eye drops to be transferred to the conjunctiva, which is the site of action. Means an agent.

(Explanation of Preferred Embodiment)
Hereinafter, preferred embodiments of the present invention will be described. It is understood that the embodiments provided below are provided for a better understanding of the invention and the scope of the invention should not be limited to the following description. Therefore, it is clear that a person skilled in the art can appropriately make modifications within the scope of the present invention in consideration of the description in the present specification. It is also understood that the following embodiments may be used alone or in combination.

The liquid preparation for ophthalmology of the present invention contains brimonidine and / or a salt thereof, and further contains a preservative and amino acids.

Examples of the salt of brimonidine include any salt as long as it is pharmaceutically acceptable. Pharmaceutically acceptable salts of brimonidine include hydrochloride, sulfate, phosphate, acetate, citrate, oxalate, malonate, salicylate, malate, fumarate, succinate, Examples thereof include ascorbate, maleate, methanesulfonate, tartrate and other inorganic carboxylates well known to those skilled in the art, preferably tartrate.

In the present invention, the low concentration brimonidine refers to brimonidine having a concentration of 0.05 w / v% or less. As an example, the upper limit of the concentration may be 0.04 w / v% or 0.03 w / v% from the viewpoint of preventing side effects. The lower limit of the concentration is not limited as long as brimonidine is contained, but 0.01 w / v% may be used. As an example, in view of the effect of this drug, 0.015 w / v% or 0.02 w / v. % May be used.

In the present invention, the preservative is formulated from the viewpoint of maintaining the quality of the liquid preparation for ophthalmology. As the preservative, any component that can be used in eye drops, such as a surfactant, can be used. Surfactants are thought to act on bacterial cell membranes and exert bactericidal action. Surfactants are classified into ionic surfactants (anionic, cationic, amphoteric) and nonionic surfactants, and some of them are known to exhibit high bactericidal action. Has been done. A surfactant having a bactericidal action can be particularly referred to as a bactericidal surfactant. Examples of the bactericidal surfactant include a cationic surfactant, an anionic surfactant, and an amphoteric surfactant. Among them, the cationic surfactant and the amphoteric surfactant have a high bactericidal action. Examples of the cationic surfactant having a high bactericidal action include benzalkonium salt, benzethonium salt, dialkyldimethylammonium salt, and polyhexamethylene biguanide salt. Examples of the amphoteric tenside agent having high bactericidal properties include alkylpolyaminoethylglycine salts. The salt of the surfactant can be appropriately selected, and examples thereof include hydrochlorides, chloride salts, and sulfates. The concentration of the preservative can be appropriately determined from the viewpoint of use in the liquid preparation for ophthalmology. As an example, it can be used at a concentration of 0.001 w / v% to 0.1 w / v%, preferably 0.005 w / v% to 0.05 w / v%.

On the other hand, when a preservative is added to an ophthalmic liquid preparation containing brimonidine and / or a salt thereof, the conjunctival transferability of brimonidine and / or a salt thereof may be reduced. Examples of the preservative capable of reducing the conjunctival transferability of brimonidine and / or a salt thereof include bactericidal surfactants.

Examples of the additive to be added to the liquid preparation for ophthalmology of the present invention include amino acids or salts thereof. Amino acids include amino acids and substances other than amino acids that have a sulfonic acid group instead of the carboxyl group of the amino acid, such as taurine. Examples of amino acids include proteinogenic amino acids such as glycine, alanine, methionine, valine, threonine, glutamine, glutamic acid, aspartic acid, aspartic acid, cysteine, histidine, isoleucine, leucine, lysine, phenylalanine, tryptophan, arginine, proline and tyrosine. , Serin. As the amino acid, an acidic amino acid such as glutamic acid or aspartic acid is preferable, and even more preferably aspartic acid. For acidic amino acids, alkali metal salts such as sodium salts or potassium salts can be used. As an example, potassium aspartate can be incorporated into the liquid preparation for ophthalmology of the present invention. The amino acids other than glycine used in the present invention may be L-form amino acids, D-form amino acids, or both. Only one type of amino acid may be used, or a plurality of types may be used in combination. Further, amino acids and taurine may be used in combination. When amino acids, especially potassium aspartate and / or taurine, are added to an ophthalmic liquid formulation containing brimonidine and / or a salt thereof, the translocation of brimonidine and / or a salt thereof, which is reduced by the addition of a preservative, is reduced. It is improved and the light stabilizing effect is further exhibited.

The concentration of amino acids can be appropriately selected according to the type thereof, and can be blended at 0.01 w / v% to 10.0 w / v% as an example. As the upper limit of the concentration of amino acids, it is preferable to use 5 w / v% from the viewpoint of safety to the eyes, more preferably 2.5 w / v%, and even more preferably 1.0 w / v%. Can be done. As the lower limit of the amino acid concentration, 0.05 w / v% can be used, and more preferably 0.1 w / v% can be used from the viewpoint of exerting the conjunctival transfer promoting effect or the photostabilizing effect.

The conjunctiva is a membrane that covers the sclera, which is the white of the eye, and also covers the inside of the eyelid, and is mainly composed of conjunctival epithelial cells. The epithelial layer of the conjunctiva contains blood vessels, fibrous tissue, and lymphatic vessels. The conjunctiva is in contact with the cornea at the boundary between the white and black eyes, and the cornea and conjunctiva form the outermost layer of the eye exposed to the outside world. Since the conjunctiva is exposed to the outside world, it is easily attacked by bacteria and viruses, and inflammation is likely to occur. Even when inflammation does not occur, lack of sleep and overuse of the eyes increase blood flow to supply oxygen and nutrients to the eyes, resulting in redness. In the present invention, in order for brimonidine and / or a salt thereof to exert the effects of alleviating redness, reducing redness or whitening of the eyes, the active ingredient of the instilled preparation reaches the capillaries in the conjunctiva and acts. It is necessary to do.

Corneal epithelial cells and conjunctival epithelial cells each form tight junctions between cells to form a hydrophobic membrane resulting from the cell membrane. This limits the permeation of water-soluble drugs through the cornea and conjunctiva. The transferability of the instilled drug through the cornea and conjunctiva is determined by measuring the drug concentration in the aqueous humor and the drug concentration in the conjunctiva after instillation, but it is difficult to measure in humans and animal experiments. The analysis is performed by the prediction model via. As a simple method for measuring the intraocular transfer of a drug, a method based on an octanol / water partition coefficient is known. The octanol / water partition coefficient can be used to evaluate not only intraocular transferability but also conjunctival transferability. Specifically, the ophthalmic solution is mixed with octanol saturated with water, and the amount of the drug present in the octanol layer (also referred to as an oil layer) after mixing is used as the transfer amount. The larger the transfer amount, the higher the conjunctival transferability of the drug. Can be evaluated as.

In the present invention, the liquid preparation for ophthalmology is an aqueous liquid preparation based on water, but may further contain any liquid base that can be used for eye drops. The liquid preparation for ophthalmology of the present invention is prepared to have a pH and osmotic pressure acceptable for eye drops. The pH of the liquid preparation for ophthalmology can be adjusted to 5.0 to 9.0 by using a pH adjuster, and is 5.5 to 8.5 as an example. As an example, it can be adjusted to 6.0 to 8.0. As an example of the osmotic pressure ratio of the liquid preparation for ophthalmology, the amount of the component added to the liquid preparation for ophthalmology is adjusted so as to be preferably 0.5 to 2.5, more preferably 0.7 to 1.5.

The liquid preparation for ophthalmology of the present invention is preferably an eye drop. The liquid preparation for ophthalmology of the present invention may be a liquid preparation that relieves or suppresses red eye. Relieving or suppressing red eye refers to increasing the whiteness of the white part of the eye, and can also be referred to as eye whitening. From the viewpoint of alleviating or suppressing red eye, the liquid ophthalmic preparation of the present invention preferably contains a low concentration of brimonidine and / or a salt thereof.

For liquid formulations with low photostability, a light-shielding container can be used. However, eye drops are used for a certain period of time after opening. If a light-shielding container is used as the eye drops, it is difficult to confirm the residual amount and changes in the contents. Therefore, it is desired to use a transparent container for the eye drops. Therefore, it is important to provide a highly photostable preparation. Further, a colored transparent container can be used instead of the light-shielding container.

The liquid preparation for ophthalmology of the present invention can contain any component that can be used for eye drops as long as the effect of the present invention is not impaired. Apart from brimonidine tartrate, which is the active ingredient of the present invention, any active ingredient and any ingredient such as additives may be contained. Such optional ingredients include decongestants, focus control function improvers, anti-inflammatory / astringent agents, antihistamines, vitamins, water-retaining / nutritional ingredients, sulfa drugs, preservatives, pH regulators, tonicity agents, and thickening agents. Agents, antioxidants, solubilizers, stabilizers, surfactants, fragrances or refreshing agents, etc., but are not intended to be limited thereto. Only one kind of these active ingredients and additives may be used from each category, or a plurality of kinds may be used in combination. Although optional components are described below, they may be used for the purpose of actions other than those listed. For example, ethanol used as a refreshing agent may be added to an ophthalmic liquid preparation as a preservative. The amino acids and preservatives used in the present invention are listed as examples of optional components, but this does not mean that these components are used arbitrarily, and the same or different components are different. It means that it can be blended for the purpose.

Vitamins are a general term for organic compounds other than carbohydrates, proteins, and lipids that cannot synthesize a sufficient amount of nutrients necessary for the survival or growth of an organism in the body of the organism. Vitamins are roughly classified into water-soluble vitamins and fat-soluble vitamins. Examples of water-soluble vitamins include vitamin Bs and vitamin C (ascorbic acid). Examples of fat-soluble vitamins include vitamin A, vitamin D, vitamin E, and vitamin K. The over-the-counter drug manufacturing (import) approval standard stipulates vitamins to be blended in eye drops, and from this viewpoint, vitamin A, vitamin B, and vitamin E are particularly preferable.

As vitamin A, retinol and related substances may be used. Retinol-related substances include retinal, retinoic acid, retinol palmitate and other retinoids such as isotretinoin, alitretinoin, acitretin, etretinate, adapalene, tazarotene, bexarotene and the like. Retinol palmitate ester and retinol acetate ester are preferable from the viewpoint of blending as eye drops. Since vitamin A acts on epithelial cells and induces proliferation, it can be added to eye drops for the purpose of protecting the cornea and conjunctiva. It can also be added to eye drops for the treatment of ophthalmic diseases such as night blindness, dry conjunctival disease, dry corneal disease, and keratomalacia.

As the B vitamins, vitamin B1 (thiamin and the like), vitamin B2, vitamin B3 (niacin and the like), vitamin B5, vitamin B6, vitamin B7 (biotin and the like), vitamin B9 (folic acid and the like) and vitamin B12 can be used. Vitamins include derivative provitamins and pharmaceutically acceptable salts. Among the B vitamins, vitamins B2, B5, B6 and B12 are particularly preferable from the viewpoint of being blended in eye drops.

As the vitamin B2, riboflavin, riboflavin phosphate, riboflavin butyrate, riboflavin acetate, flavin adenine dinucleotide, flavin mononucleotide, pharmaceutically acceptable salts thereof and the like can be used. Examples of the salt include sodium salts and potassium salts. Flavin adenine din-wook clay otido sodium is preferable from the viewpoint of being formulated as an eye drop. Vitamin B2 is directly involved in oxidative reduction, and when used as an eye drop, promotes enzymatic respiratory metabolism of corneal and conjunctival cells, and has a protective effect on the cornea and conjunctiva. Vitamin B2 can also be added to eye drops for the treatment of keratitis presumed to be associated with vitamin B2 deficiency or metabolic disorders.

As vitamin B5, panthenol, pantothenic acid or derivatives thereof or salts thereof can be used. As an example, in addition to panthenol and pantothenic acid, as derivatives or salts thereof, pantethine, pantetheine, pantotheneal alcohol, pantotheneyl ethyl ether, pantetheine pantothenic acid alcohol, calcium pantothenate, sodium pantothenate and the like can be mentioned. From the viewpoint of being used as eye drops, panthenol, calcium pantothenate, and sodium pantothenate are preferable as vitamin B5.

As vitamin B6, pyridoxal, pyridoxamine, pyridoxine or pharmaceutically acceptable salts thereof can be used. From the viewpoint of being used as eye drops, pyridoxine hydrochloride is preferable. Vitamin B6 is involved in protein metabolism as a coenzyme of amino acid decarboxylase and transaminase in vivo, and can be added to eye drops to suppress eye fatigue.

Vitamin B12 is a compound having a structure in which cobalt is coordinated to the choline ring, and specific examples thereof include cyanocobalamin, mecobalamin (methylcobalamin), hydroxocobalamin, adenosylcobalamin, hydroxocobalamin hydrochloride, and hydroxocobalamin acetate. Vitamin B12 can be added to eye drops for pharmacological actions such as improvement of tired eyes and eyestrain.

As vitamin Es, tocopherols, tocotrienols, tocofersolan, or derivatives thereof can be used. The tocopherol and tocotrienol may be any of α-, β-, γ-, and δ-, and may be any of d-form and dl-form. From the viewpoint of being used as eye drops, examples thereof include d-α-tocopherol acetate and dl-α-tocopherol acetate.

Vitamin C includes ascorbic acid or a salt thereof. Vitamin Ds include vitamin D2 (ergosterol, ergocalciferol), D3 (7-dehydrocholesterol), previtamin D3 (cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol). Ferrol), calcitronic acid), vitamin D4 (dihydroergocalciferol), vitamin D5 (dihydrotaxterol, calcipotriol, tacalcitol, paricalcitol) and the like. Examples of vitamin Ks include phylloquinone (K1), menaquinone (K2), and menadione (K3).

As the decongestant, epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine, or salts thereof may be used.

As the focus adjusting function improving agent, neostigmine methylsulfate can be used.

As the anti-inflammatory / astringent agent, ε-aminocaproic acid, allantin, velverine or a salt thereof, azulene sulfonic acid or a salt thereof, glycyrrhizinic acid or a salt thereof, zinc sulfate, zinc lactate, lysozyme chloride, or a salt thereof may be used.

As the antihistamine, diphenhydramine hydrochloride, chlorpheniramine maleate, or salts thereof may be used.

As the water retention / nutrition component, amino acids or salts thereof and sodium chondroitin sulfate can be used. In the present invention, amino acids are blended in an ophthalmic liquid preparation for the purpose of improving stability and conjunctival transferability, but the same or different amino acids may be blended as water-retaining / nutritional components. As the amino acids or salts thereof, the amino acids are not only amino acids but also substances having a sulfate group instead of the carboxyl group of the amino acid, for example, taurine. Examples of amino acids include glycine, alanine, methionine, valine, threonine, glutamine, glutamic acid, asparagine, aspartic acid, cysteine, histidine, isoleucine, leucine, lysine, phenylalanine, tryptophan, arginine, proline, tyrosine and serine. .. Amino acids preferably include aspartic acid, methionine and glycine. The amino acids other than glycine may be L-form amino acids, D-form amino acids, or DL-form amino acids.

As the sulfa agent, sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, and sulfisomidin sodium can be used.

Preservatives include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, benzalconium chloride, chlorobutanol, sodium chlorate, benzododecinium bromide, chlorhexidine. Gluconate, sorbate, sodium dehydroacetate, benzoate, benzyl alcohol, alkylpolyaminoethylglycine hydrochloride, polyhexamethylenebiguanide, boric acid, boarite and the like can be used.

Examples of the pH adjusting agent include a citrate buffer, an acetate buffer, a carbon dioxide buffer, a borate buffer, a phosphate buffer, and the like, as well as hydrochloric acid, acetic acid, boric acid, carbonic acid, sulfuric acid, and phosphoric acid. Acids such as citric acid and tartrate, and bases such as sodium hydroxide, sodium hydrogencarbonate, sodium carbonate, triethanolamine and monoethanolamine can be used.

Examples of the tonicity agent include sugars and salts, and examples of the salts include sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, and the like. Sodium thiosulfate, magnesium sulfate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate and the like can be used. As the saccharide, any monosaccharide or polysaccharide can be used, and as an example, glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like can be used.

As the thickener, sodium chondroitin sulfate, polyvinyl alcohol, carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, alginic acid, hyaluronic acid, polyvinylpyrrolidone and the like or salts thereof can be used.

As the solubilizing agent, nonionic surfactants such as polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, tyroxapol, and pluronic; and polyhydric alcohols such as glycerin and macrogol can be used.

As the stabilizer, for example, polyvinylpyrrolidone, sulfite, monoethanolamine, glycerin, propylene glycol, polyethylene glycol, cyclodextrin, dextran, ascorbic acid, edetate, taurine, tocopherol and the like can be used.

Examples of the surfactant include nonionic surfactants such as tyroxalol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, and octoxinol; alkyldiaminoethylglycine salts. , Amphoteric surfactants such as lauryldimethylaminoacetic acid betaine; anionic surfactants such as alkyl sulfates, N-acyltaurine salts, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates; alkylpyridinium salts , Alkylamine salt, benzalconium salt, polyhexamethylene biguanide salt and other cationic surfactants can be used. In particular, benzalkonium salt, alkyldiaminoethylglycine salt, polyhexamethylene biguanide salt and the like can be used as a bactericidal surfactant.

Examples of the fragrance or refreshing agent include menthol, ethanol, camphor, geraniol, borneol, menthol, ryuno, uikyo oil, cool mint oil, spearmint oil, peppermint water, peppermint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil, etc. Can be used.

All references referred to herein are incorporated herein by reference in their entirety.

The embodiments of the present invention described below are for purposes of illustration only and do not limit the technical scope of the present invention. The technical scope of the invention is limited only by the description of the claims. Modifications of the present invention, for example, addition, deletion and replacement of the constituent elements of the present invention may be made on condition that the gist of the present invention is not deviated.

[Test Example 1] Measurement of the amount of brimonidine tartrate distributed to the octanol layer / aqueous layer 1. Preparation of test ophthalmic solution Add boric acid (Fujifilm Wako Pure Chemical Industries, Ltd.) and brimonidine tartrate (Hinewy Pharma. Tech. Co., Ltd) to purified water to dissolve it, and then add potassium L-aspartate (Tokyo) as appropriate. Kasei Kogyo Co., Ltd.) and / or Taurine (Fuji Film Wako Pure Chemical Industries, Ltd.) is added and dissolved, followed by benzalconium chloride (Fuji Film Wako Pure Chemical Industries, Ltd.) and alkyldiaminoethylglycine hydrochloride (Fuji Film). Wako Pure Chemical Industries, Ltd.) or polyhexamethylene viguanide (Carbosys Limited) was added and dissolved. After dissolution, the pH is adjusted with a pH adjuster (1 mol / L hydrochloric acid or 0.1 N NaOH), and the solution is prepared with purified water to prepare a solution having the composition shown in Tables 1 to 5, and Comparative Examples 1 to 7. And the test ophthalmic solutions of Examples 1 to 17 were obtained. The numerical values in the table are w / v% excluding pH and the rate of increase.

2. 2. Operation of octanol transfer test 1. The test ophthalmic solution prepared in 1. and 1-octanol (Nacalai Tesque Co., Ltd.) were mixed based on the following operation to obtain an aqueous layer sample:
1) A plastic centrifuge tube was filled with 2.5 mL of 1-octanol saturated with each test ophthalmic solution and water.
2) Mixing was performed with a vortex mixer (VX100, Labnet International) for 30 seconds.
3) Shaking was performed for 30 minutes with a shaker (MW-1, AS ONE) (300 times / minute) that stirs in the vertical direction.
4) Shaker was shaken in a horizontal shaker (Universal Shaker SHK-U4, AGC technoglass) (120 pm / min) for 24 hours or more.
5) Mixing was performed with a vortex mixer (VX100, Labnet International) for 30 seconds.
6) After separating the octanol layer and the aqueous layer by centrifugation (LC-120, Tomy Seiko) (3000 rpm, 10 minutes), the aqueous layer was collected and used as a mixed aqueous layer sample.

3. 3. Measurement of brimonidine tartrate content Brimonidine using high performance liquid chromatography (HPLC) method for each test ophthalmic solution prepared in 1. and the mixed aqueous layer sample obtained in 2. The tartrate content was measured.
Column: Inner diameter 4.6 mm x length 75 mm Octadecylsilylated silica gel ("SymmeteryC18 3.5" manufactured by Waters)
Detector: Ultraviolet-visible absorptiometer Measurement wavelength: 264nm
Mobile phase: Ammonium dihydrogen phosphate (5.175 g) was dissolved in 900 mL of water, and 100 mL of acetonitrile for liquid chromatography was added.

［式中、Ｃ_sampleは実施例又は比較例の試験点眼液とオクタノールとを混合後、オクタノール層へ移行したブリモニジン酒石酸塩含量、Ｃ_比較例は、比較例の試験点眼液とオクタノールとを混合後、オクタノール層へ移行したブリモニジン酒石酸塩含量とした。］
比較対象として、比較例１～７をそれぞれ用いた。 The brimonidine tartrate content transferred to the octanol layer by mixing octanol with each test ophthalmic solution is the brimonidine tartrate content in each test ophthalmic solution obtained by measurement and the brimonidine tartrate content in the mixed aqueous layer sample. Obtained from the difference. The rate of increase in the amount of brimonidine tartrate transferred to the octanol layer (C _rate ) due to the inclusion of amino acids was calculated according to the following formula.

[In the formula, C _sample is the content of brimonidine tartrate transferred to the octanol layer after mixing the test ophthalmic solution of Example or Comparative Example with octanol, and C _{Comparative Example} is after mixing the test ophthalmic solution of Comparative Example and octanol. , The brimonidine tartrate content transferred to the octanol layer. ]
Comparative Examples 1 to 7 were used as comparison targets.

Addition of the preservatives benzalkonium chloride, alkyldiaminoethylglycine hydrochloride or polyhexamethylene biguanide to the test ophthalmic solution containing brimonidine tartrate reduced the amount of brimonidine tartrate transferred to the octanol layer. On the other hand, it was shown that the decrease in the amount of brimonidine tartrate transferred to the octanol layer can be suppressed by further adding potassium L-aspartate or taurine.

[Test Example 2] Measurement of stability of brimonidine tartrate 1. Preparation of test ophthalmic solution Boric acid (Fujifilm Wako Pure Chemical Industries, Ltd.) and brimonidine tartrate (Hinewy Pharma. Tech. Co., Ltd.) were added and dissolved in purified water, and L-aspartic acid was added as an appropriate amino acid. Add potassium (Tokyo Kasei Kogyo Co., Ltd.) or taurine (Fujifilm Wako Pure Chemical Industries, Ltd.) to dissolve, then benzalconium chloride (Fujifilm Wako Pure Chemical Industries, Ltd.) and alkyldiaminoethylglycine hydrochloride as preservatives. Salt (Fuji Film Wako Pure Chemical Industries, Ltd.) or polyhexamethylene biguanide (Carbocinth Limited) was added and dissolved. After dissolution, the pH was adjusted with a pH adjuster (1 mol / L hydrochloric acid or 0.1 N NaOH) to prepare a solution having the composition shown in Tables 6 to 8, and Comparative Examples 1, 3 and 8 and Examples 2 to 4 were prepared. Test ophthalmic solutions of 7 to 21 were obtained. The numerical values in the table are w / v% excluding pH and residual rate.

2. 2. Optical stability test 1. Enclose 5 mL of the test ophthalmic solution prepared in 1 in a glass ampoule, place it in a photostability test device (LT-120A-WCD, manufactured by Nagano Science Co., Ltd.), and expose it to white light of 600,000 lux · hr to expose the deteriorated product. Obtained. The brimonidine tartrate content of the deteriorated product and the pre-deteriorated product of each test ophthalmic solution of Comparative Example and Example was measured by a high performance liquid chromatograph system (HPLC, manufactured by Shimadzu Corporation) under the following conditions. The residual rate (%) of brimonidine tartrate was calculated according to the formula shown below.

3. 3. Measurement of Brimonidine Tartrate Content The brimonidine tartrate content of each test ophthalmic solution was measured using high performance liquid chromatography (HPLC) under the following conditions.
Column: Inner diameter 4.6 mm x length 15 cm Octadecylsilylated silica gel ("AA12S05-1506WT" manufactured by YMC Co., Ltd.)
Detector: Ultraviolet absorptiometer (measurement wavelength: 264 nm)
Column temperature: 40 ° C
Mobile phase: Dissolve 5.175 g of ammonium dihydrogen phosphate in 900 mL of water and add 100 mL of acetonitrile for liquid chromatography.
Flow velocity: Approximately 1 mL / min

By adding the preservatives benzalkonium chloride, alkyldiaminoethylglycine hydrochloride or polyhexamethylene biguanide, and the amino acids potassium L-aspartate or taurine to the test ophthalmic solution containing brimonidine tartrate. The photostability of brimonidine tartrate was improved.

[Test Example 3] Measurement of the amount of brimonidine tartrate transferred to the rabbit conjunctiva 1. Preparation of test ophthalmic solution Boric acid (Fujifilm Wako Pure Chemical Industries, Ltd.), borax (Nakalitesk Co., Ltd.) and brimonidine tartrate (Hinewy Pharma. Tech. Co., Ltd.) were added to and dissolved in purified water to dissolve them. Further, benzalconium chloride (Fujifilm Wako Pure Chemical Industries, Ltd.) and taurine (Fujifilm Wako Pure Chemical Industries, Ltd.) were added and dissolved as appropriate. After dissolution, the pH was adjusted with a pH adjuster (1 mol / L hydrochloric acid or 0.1N NaOH) in all formulations to prepare the solutions shown in Table 9, and the tests of Comparative Example 9, Comparative Example 10 and Example 22 were carried out. Ophthalmic solution was obtained. The values in the table are w / v% excluding pH.

2. 2. Conjunctival transfer test 1. The test ophthalmic solution prepared in the above was subjected to a conjunctival transfer test as 4 cases in each group according to the following operation:
1-1) Tube1: Four in each group, the test ophthalmic solution was dispensed into each 1 mL sample tube (1.5 mL microtube, Zartstat).
1-2) Tube2: Four samples in each group and a sample tube with a filter (Ultrafree-MC-GV 0.45 μm, millipore) were prepared.
2) A rabbit excised eyeball (Kitayama Labes) was obtained and the conjunctiva was cut out.
3) The conjunctiva was washed by immersing it in physiological saline (Otsuka raw food injection, Otsuka Pharmaceutical Factory).
4) Moisture on the surface was lightly wiped off with a Kimwipe, and the weight of the conjunctiva was measured.
5) After measuring the weight of the conjunctiva, the conjunctiva was put into 1-1) Tube1 and shaken at 1,500 rpm with a shaker (block bath shaker-MyBL-100CS, AS ONE) for 5 minutes.
6) The conjunctiva was taken out from Tube1 of 5).
7) Take 300 μL of the sample from Tube1 of 6) excluding the conjunctiva, add it to 1-2) Tube2, and centrifuge it with a desktop micro high-speed centrifuge (CT-12RE, Hitachi Koki) (15,000 rpm, 10 minutes). , 4 ° C), and the filtrate was used as a sample.

［式中、Ｃ_sampleは実施例又は比較例のブリモニジン酒石酸塩の結膜移行量、Ｃ_比較例9は比較例９のブリモニジン酒石酸塩の結膜移行量とした。］ 3. 3. Determination of conjunctival transfer amount (i) Test ophthalmic solution that does not soak the conjunctiva and (ii) 2. The brimonidine tartrate content of the sample obtained in the conjunctival transfer test 7) was measured by high performance liquid chromatography (HPLC), and the amount of conjunctival transfer per sample was determined from the difference between (i) and (ii). 2. 2. From the conjunctival weight measured in the conjunctival transfer test 4), the content of brimonidine tartrate transferred per 1 g of conjunctiva was determined for each individual, and the average value of the four cases was taken as the conjunctival transfer amount.
The rate of increase in the amount of brimonidine tartrate transferred to the conjunctiva (C _rate ) due to the addition of taurine was calculated according to the following formula.

[In the formula, C _sample was the conjunctival transfer amount of brimonidine tartrate of Example or Comparative Example, and C _{Comparative Example 9} was the conjunctival transfer amount of brimonidine tartrate of Comparative Example 9. ]

Among the combinations of preservatives and amino acids whose transferability to the octanol layer (lipophilicity) was investigated in Test Example 1, a typical combination of taurine and benzalkonium chloride was transferred to the actual conjunctiva. Examined. Similar to the result of transferability to the octanol layer, the addition of benzalconium chloride reduces the amount of brimonidine tartrate transferred to the conjunctiva, but the addition of taurine suppresses the decrease in the amount of brimonidine tartrate transferred to the conjunctiva. Was done. Therefore, it can be presumed that the combination of the preservative and amino acids with improved transferability to the octanol layer in Test Example 1 also improves transferability to the rabbit conjunctiva.

Claims (5)

An ophthalmic liquid preparation containing 0.01 w / v% to 0.05 w / v% brimonidine and / or a salt thereof, a preservative, and amino acids. The liquid preparation for ophthalmology according to claim 1, wherein the preservative is a bactericidal surfactant. The liquid preparation for ophthalmology according to claim 2, wherein the bactericidal surfactant is selected from the group consisting of a benzalkonium salt, an alkyldiaminoethylglycine salt, and a polyhexamethylene biguanide salt. The ophthalmic liquid preparation according to any one of claims 1 to 3, wherein the amino acids are at least one selected from aspartic acid and / or a salt thereof and taurine. The liquid preparation for ophthalmology according to any one of claims 1 to 4, wherein the concentration of amino acids is 0.01 w / v% to 10 w / v%.